Pharmacokinetics and pharmacodynamics of Phor21-betaCG(ala), a lytic peptide conjugate.
Phor21-betaCG(ala), a 36-amino acid peptide comprised of a lytic peptide (Phor21) conjugated to a modified 15-amino acid segment of the beta-chain of chorionic gonadotropin (betaCG(ala)), selectively kills cancer cells that over-express luteinizing hormone/chorionic gonadotropin (LH/CG) receptors by disrupting cellular membrane structure. These studies were designed to further characterize its in-vitro inhibition and in-vivo destruction of prostate cancer cells, biostability and pharmacokinetics to determine its pharmacokinetic and pharmacodynamic profile. Inhibitory effects of Phor21-betaCG(ala) were tested in PC-3 and Caco-2 cells as well as in nude mice bearing PC-3 cells transfected with the luciferase gene (PC-3.luc). Plasma stability, protease hydrolysis and pharmacokinetics of Phor21-betaCG(ala) were measured by using liquid chromatography mass spectrometry (LC/MS/MS). Phor21-betaCG(ala) selectively inhibited proliferation in-vitro and in-vivo metastases of PC-3 cells. Phor21-betaCG(ala) was relatively stable in mouse, rat, dog and human plasma. Its degradation was partially due to protease hydrolysis and thermodynamic catalysis. Intravenous administration of Phor21-betaCG(ala) showed its blood C(max) and AUC(0-->infinity) around the in-vitro effective levels. In the tested rodents, Phor21-betaCG(ala) displayed a moderate volume of distribution at steady state (Vd(ss)) and slow clearance (Cl) in the rodents. In conclusion, Phor21-betaCG(ala) displayed promising in-vitro and in-vivo anti-cancer activity with favourable pharmacokinetics, and may offer a novel approach to metastatic cancer chemotherapy.
Jia
Lee
L
The National Cancer Institute/NIH, Rockville, MD 20852, USA. jiale@mail.nih.gov
Noker
Patricia E
PE
Piazza
Gary A
GA
Leuschner
Carola
C
Hansel
William
W
Gorman
Gregory S
GS
Coward
Lori U
LU
Tomaszewski
Joseph
J
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002853:Chromatography, Liquid; D004285:Dogs; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000188:drug therapy; D010455:Peptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution; D014162:Transfection
D000970:Antineoplastic Agents; D010455:Peptides; C533905:Phor21-betaCG(ala) peptide; D008156:Luciferases